Ceftolozane is a cephalosporin antibacterial agent of the beta-lactam class (β-lactams), also referred to as CXA-101, FR264205, or by chemical names such as (6R,7R)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-carboxylic acid, 3-[[4-[[[(2-aminoethyl)amino]carbamoyl]amino]-2,3-dihydro-3-imino-2-methyl-1H-pyrazol-1-yl]methyl]-7-[[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-8-oxo; or (6R,7R)-3-[(5-amino-4-{[(2-aminoethyl)carbamoyl]amino}-1-methyl-1H-pyrazol-2-ium-2-yl)methyl]-7-({(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(1-carboxy-1-methylethoxy)imino]acetyl}amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, and 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-{3-amino-4-[3-(2-aminoethyl)ureido]-2-methyl-1-pyrazolio}methyl-3-cephem-4-carboxylate. Ceftolozane sulfate is a pharmaceutically acceptable ceftolozane salt of formula (VI) that can be formulated for intravenous administration or infusion.

Ceftolozane sulfate is also referred to as: 1H-Pyrazolium, 5-amino-4-[[[(2-aminoethyl)amino]carbonyl]amino]-2-[[(6R,7R)-7-[[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1-methyl-,sulfate (1:1); or 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-{3-amino-4-[3-(2-aminoethyl)ureido]-2-methyl-1-pyrazolio}methyl-3-cephem-4-carboxylic acid hydrogen sulfate. Ceftolozane can be obtained as disclosed in U.S. Pat. No. 7,129,232 and in Toda et al., “Synthesis and SAR of novel parenteral anti-pseudomonal cephalosporins: Discovery of FR264205,” Bioorganic & Medicinal Chemistry Letters, 18, 4849-4852 (2008), incorporated herein by reference. The antibacterial activity of ceftolozane is believed to result from its interaction with penicillin binding proteins (PBPs) to inhibit the biosynthesis of the bacterial cell wall which acts to stop bacterial replication.
Referring to FIG. 1, synthesis of ceftolozane can be performed via activation of the thiadiazolyl-oximinoacetic acid derivative (I) with methanesulfonyl chloride and K2CO3 in DMA at 10° C., followed by coupling with the 7-aminocephem (II) by means of Et3N in cold EtOAc/H2O, affords amide (III). See U.S. Pat. Nos. 7,129,232 and 7,192,943, as well as Toda et al., “Synthesis and SAR of novel parenteral anti-pseudomonal cephalosporins: Discovery of FR264205,” Bioorganic & Medicinal Chemistry Letters, 18, 4849-4852 (2008). Substitution of the allylic chloride of compound (III) with 4-[(N-Boc-aminoethyl)carbamoylamino]-1-methyl-5-tritylaminopyrazole (IV) in the presence of 1,3-bis(trimethylsilyl)urea (BSU) and KI in DMF then affords the protected pyrazolium adduct (V), which, after full deprotection with trifluoroacetic acid in anisole/CH2Cl2, can be isolated as the hydrogensulfate salt by treatment with H2SO4 in i-PrOH/H2O.
The pyrazolyl urea intermediate compound (IV) of FIG. 1 can be prepared from compound (VII) through a sequence of five steps, including one transition metal-catalyzed hydrogenation, as depicted in FIG. 2. Treatment of 5-amino-1-methylpyrazole (VII) with NaNO2/HCl in water at 5° C. gives the 4-nitrosopyrazole derivative (VIII), which can be reduced to the diaminopyrazole (IX) by catalytic hydrogenation over Pd/C in the presence of H2SO4. Selective acylation of the 4-amino group of compound (IX) with phenyl chloroformate in the presence of NaOH in H2O/dioxane at 10° C. then yields the phenyl carbamate (X). After protection of the free amine group of carbamate (X) with chlorotriphenylmethane in the presence of Et3N in THF, the resulting N-trityl derivative (XI) can be coupled with N-Boc-ethylenediamine in the presence of Et3N in DMF to afford pyrazolyl urea (IV). There is a need for methods of preparing compound (IV) having fewer steps and avoiding the use of transition metal catalysts. There is also a need for chemical intermediates useful in such methods.